ABSTRACT
Congenital hypothyroidism (CH) will cause cognitive impairment in the condition of delayed treatment. The hippocampus is one of the most affected tissues by CH, in which the functional structures of hippocampal neurons manifest deficiency due to aberrant expression of effector molecules. The Ca2+/Calmodulin-dependent protein kinase, CaMKIV, is downregulated in the hippocampal neurons, influencing the growth of dendritic spines in response to CH. However, the underlying mechanism is not fully elucidated. In the present study, the early growth response factor 3 (EGR3) was regulated by CaMKIV in the hippocampal neurons of CH rat pups, as was analyzed by transcriptome sequencing and in vitro cell experiments. EGR3 localized within hippocampal neurons in CA1, CA3, and dentate gyrus regions. Deficient EGR3 in the primary hippocampal neurons significantly reduced the density of dendritic spines by downregulating the expression of BDNF, and such effects could be rescued by supplementing recombinant BDNF protein. Taken together, CH mediates cognitive impairment of pups through the inactivation of CaMKIV in the hippocampal neurons, which decreases the expression of EGR3 and further reduces the production of BDNF, thereby impairing the growth of dendritic spines. Identifying CaMKIV/EGR3/BDNF pathway in the hippocampal neurons in the context of CH will benefit the drug development of intellectual disability caused by CH.
ABSTRACT
Metastasis is the most frequent cause of death in patients with breast cancer. Tip30/CC3 gene is a putative metastasis suppressor gene, which was first identified by a differential display analysis of messenger RNA from the highly metastatic human variant small cell lung carcinoma (SCLC) versus less metastatic classic SCLC cell lines. The aim of this study was to analyze the relationship between expression of TIP30/CC3 and clinical prognosis in 87 patients with surgically removed breast carcinoma. Tumor tissues were stained immunohistochemically with anti-TIP30/CC3 antibody. We demonstrated that the expression of TIP30/CC3 was inversely associated with axillary lymph node metastasis (P = .0008) and vascular invasion (P = .0016). Expression of TIP30/CC3 was not correlated with tumor grade, estrogen, progesterone, and P53 expression. Inhibition of TIP30/CC3 expression by RNA-mediated interference greatly enhanced breast cancer cell invasion through the extracellular matrix, whereas overexpression of TIP30/CC3 by adenovirus vector suppressed invasion through the extracellular matrix. These data supported the theory that the expression of TIP30/CC3 had a suppressive function on tumor metastasis. In summary, the decrease in expression of TIP30/CC3 is related to metastasis and may represent a new prognosticator in breast carcinoma.
Subject(s)
Acetyltransferases/analysis , Breast Neoplasms/pathology , Transcription Factors/analysis , Tumor Suppressor Protein p53/analysis , Acetyltransferases/genetics , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Movement/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Lymphatic Metastasis , Middle Aged , Prognosis , RNA Interference , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Transcription Factors/genetics , TransfectionABSTRACT
Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The specific cellular gene alterations responsible for hepatocarcinogenesis are not well known. Previous works showed that loss of TIP30, also called CC3, a putative tumor suppressor, increased the incidence of hepatocellular carcinoma in mice, and some clinical samples of human HCC tissues had aberrant expression of TIP30. Here, we report that the introduction of TIP30 by an adenovirus vector into HCC cell lines that had decreased expressions of TIP30 inhibited cell proliferation, decreased anchorage-dependent growth, suppressed invasion through the extracellular matrix, and inhibited tumorigenesis in nude mice. Moreover, exogenous expression of Tip30 sensitized HCC cells to cytotoxic drugs and to apoptosis induced by tumor necrosis factor-related ligands in vitro. Ectopic expression of TIP30 in HCC cells enhanced p53 expression and decreased Bcl-2/Bcl-xL expression. Treatment of nude mice bearing subcutaneously established HCC tumors with a combination of an adenovirus expressing TIP30 and the cytotoxic drug 5-fluorouracil completely suppressed tumor growth and prolonged survival. In conclusion, TIP30 may play an important role in the suppression of hepatocarcinogenesis by acting as a tumor suppressor. Overexpression of TIP30 might be a promising candidate as a treatment for HCC that would increase sensitivity to chemotherapeutic drugs.